tbuckley/cabot-search huggingface dataset:
<i>XIRP2 </i>mutation as an indicator stratified patients benefit from immune checkpoint inhibitors in NSCLC.
Authors: Hualin Chen, Meilian Liu, Yiping Luo, Lele Zhao, Lingli Huang, Mingzhe Xiao, Chuang Qi, Zhixiong Yang
Journal: Journal of Clinical Oncology (2022)

e14573 Background: Immune checkpoint inhibitors (ICIs), targeting the programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1) or cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have demonstrated impressive anti-tumor efficacy in multiple tumors, particularly non-small cell lung cancer (NSCLC). However, only a minority of patients could clinically benefit from the ICIs. Therefore, it is of vital clinical significance to explore underlying predictive biomarkers to identify to identify these most potentially ICIs-benefitable patients. Xin-actin binding repeat containing 2 (XIRP2) encodes an actin-cross-linking protein that was previously reported to be significantly mutated in breast cancer metastases. However, its role in lung cancer immunotherapy remains unknown. Here we aimed to explore the association between XIRP2 and ICIs. Methods: 165 NSCLC patients from three public immunotherapy cohorts (Hellmann 2018, Miao 2018, and Rizvi 2015 cohort) were included to analyze the association between XIRP2 gene mutation and efficacy of ICI therapy. Genomic, survival and mRNA data of NSCLC patients from the Cancer Genome Atlas (TCGA) database was used to explore the potential mechanisms of anti-tumor immunity. Results: NSCLC patients with XIRP2 mutation were significantly associated with better PFS (HR = 0.4; 95% CI, 0.21-0.75; P = 0.003) after ICIs therapy, compared with those with wide-type XIRP2. XIRP2 mutation were associated with increased TMB ( P &lt; 0.001). In the multivariable Cox proportional hazards regression model adjusted by smoking status, PD-L1 expression and TMB, the association between XIRP2 mutation and PFS remained significant (HR = 0.4; 95% CI, 0.20-0.81; P = 0.011). In contrast, no association between XIRP2 mutation and OS (LUAD: P = 0.43 ; LUSC: P = 0.17) or PFS (LUAD: P = 0.54; LUSC: P = 0.19) was observed in TCGA datasets, suggesting that XIRP2 mutation may be a predictive but not a prognostic factor in ICI treatment for NSCLC patients. Based on CIBERSORT-inferred tumor infiltrating lymphocytes from TCGA, XIRP2 mutation was significantly associated with higher M1 macrophage, CD8+ T cell, as well as lower Treg cell. Moreover, XIRP2 mutation was associated with increased TMB ( P &lt; 0.001) and neoantigen load ( P &lt; 0.001) in TCGA. Conclusions: Our results demonstrated that XIRP2 mutation is an underlying classifier that could stratify patients with NSCLC for ICIs. The role of XIRP2 in immunotherapy is needed to be further studied.
<i>NPAP1 </i>mutation as an indicator stratified patients benefit from immune checkpoint inhibitors in NSCLC.
Authors: Nuo Yang, Liwen Huang, Jun Liu, Jianji Guo, Lele Zhao, Huizi Chai, Mingzhe Xiao, Chuang Qi
Journal: Journal of Clinical Oncology (2022)

e14574 Background: Immune checkpoint inhibitors (ICIs), targeting the programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1) or cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have demonstrated impressive anti-tumor efficacy in multiple tumors, particularly non-small cell lung cancer (NSCLC). However, only a minority of patients could clinically benefit from the ICIs. Therefore, it is of vital clinical significance to explore underlying predictive biomarkers to identify to identify these most potentially ICIs-benefitable patients. Nuclear pore associated protein 1 ( NPAP1) encodes an protein is associated with the nuclear pore complex and has been previously reported as a potential prognostic biomarker for laryngeal, colorectal and lung cancers. However, its role in lung cancer immunotherapy remains unknown. Here we aimed to explore the association between NPAP1 and ICIs. Methods: 165 NSCLC patients from three public immunotherapy cohorts (Hellmann 2018, Miao 2018, and Rizvi 2015 cohort) were included to analyze the association between NPAP1 gene mutation and efficacy of ICI therapy. Genomic, survival and mRNA data of NSCLC patients from the Cancer Genome Atlas (TCGA) database was used to explore the potential mechanisms of anti-tumor immunity. Results: NSCLC patients with NPAP1 mutation were significantly associated with better PFS (HR = 0.37; 95% CI, 0.19-0.71; P = 0.002), objective response rate (ORR, 54.2% vs 28.4%; P = 0.048) and durable clinical benefit (DCB, 75.0% vs 42.6%; P= 0.003) after ICIs therapy, compared with those with wide-type NPAP1. NPAP1 mutation were associated with increased TMB ( P &lt; 0.001). In the multivariable Cox proportional hazards regression model adjusted by smoking status, PD-L1 expression and TMB, the association between NPAP1 mutation and PFS remained significant (HR = 0.46; 95% CI, 0.23-0.92; P = 0.028). In contrast, no association between NPAP1 mutation and OS (LUAD: P = 0.24 ; LUSC: P = 0.94) or PFS (LUAD: P = 0.3; LUSC: P = 0.72) was observed in TCGA datasets, suggesting that NPAP1 mutation may be a predictive but not a prognostic factor in ICI treatment for NSCLC patients. Based on CIBERSORT-inferred tumor infiltrating lymphocytes from TCGA, NPAP1 mutation was significantly associated with higher activated memory CD4+ T cell and CD8+ T cell. Moreover, NPAP1 mutation was associated with increased TMB ( P &lt; 0.001) and neoantigen load ( P &lt; 0.001) in TCGA. Conclusions: Our results demonstrated that NPAP1 mutation is an underlying classifier that could stratify patients with NSCLC for ICIs. The role of NPAP1 in immunotherapy is needed to be further studied.
Gender and early career faculty disparities in hematology and medical oncology board review lectures series.
Authors: Leen Mohammad Al-Kraimeen, Sebawe Syaj, Marah Akhdar, Hassan Mohammed Abushukair, Razan Mohty, Samer Al Hadidi
Journal: Journal of Clinical Oncology (2022)

11060 Background: Studies show that women and early career faculty members have less access to career development opportunities and leadership positions. These disparities slow the process of change and may affect leadership roles, promotions, and career advancements in academic medicine. Here, we provide the first analysis of speakers’ gender and early faculty disparities in hematology and medical oncology board review series. Methods: We performed a cross-sectional analysis of speakers at all major hematology and/or oncology board review series meetings, which were held in the United States between January 2017 and December 2021. Six major board review series were involved: Baylor/M.D. Anderson Cancer Center, the Brigham and Dana-Farber, George Washington School of Medicine and Health Sciences, Memorial Sloan Kettering Cancer Center, Seattle Cancer Care Alliance, and the American Society of Hematology. Details of the lectures were acquired via accessing brochures available on the institutions’ official websites. Data on board certification and maintenance of certificate (MOC) were obtained from the American Board of Internal Medicine (ABIM) website. We extracted the number of publications from the PubMed website (MEDLINE). Results: Our analysis included 1224 board review lectures presented by 386 speakers. Of which, 315 (81.6%) were American Board of Internal Medicine (ABIM) certified, and MOC was active in 56.1% of speakers. Females accounted for 37.7% of all speakers, with a representation of less than 50% in 5 out of 6 board review series. The least proportion of female participation was among lectures discussing malignant hematology topics (24.8%), followed by solid tumors (38.9%), and benign hematology topics (44.1%). Faculty members with more than 15 years of experience since initial certification presented more than half of the lectures. The median time from initial hematology or medical oncology certification to lecture presentation was 12.5 years and 14 years, respectively, which varied significantly among different series (p &lt; 0.001). Speakers’ median number of publications was 84. We also investigated how frequently the same speaker gave lectures. Thirteen male speakers conducted more than or equal to 10 lectures across all board review series, compared to only two female speakers who did the same. An upward trend of improvement in females participation was found at all board review conference meetings across the years. Conclusions: Our data suggest that women and early career faculty members are underrepresented in hematology and oncology board review series. Therefore, efforts should be made to ensure equal participation of them in such important activities needed to advance academic careers.
Co-occurrence of germline pathogenic variants in Chinese patients with solid tumors.
Authors: Yan Zhang, Tiantian Han, Didi Guo, Ningning Luo, Guanghua Lu, Fanfeng Bu
Journal: Journal of Clinical Oncology (2022)

10579 Background: Germline mutations play an important role in cancer risk and susceptibility. With the growing implementation of next generation sequence of multiple gene panel, an increasing number of cases that carry two or more inherited cancer-predisposing alleles in the same individual are being described. However, understanding the impact of these combined mutations on the patient's phenotype can be particularly challenging. To further understand these combined mutations, we analyze the genetic susceptibility mutations of Chinese solid tumor patients to explore the characteristics of multiple germline variants. Methods: Genetic mutations were reviewed in cancer patients who underwent hybridization capture based next-generation sequencing (NGS). The pathogenicity of germline mutations was categorized based on American College of Medical Genetics and Genomics (ACMG) guidelines, and only pathogenic and likely pathogenic variants were included in this study. Results: Germline variants were identified in 1267 individuals, including 1244 patients harbored one germline mutations and 23 patients carried ≥2 germline mutations, and there was no age difference in the two groups (57 vs 55, p = 0.62). In the ≥2 germline mutations group, genes most frequently involved were BRCA1/2 (12/47, 25.5%), CHEK2 (4/47, 5,1%), TP53(4/47, 5,1%) and MUTYH (4/47, 5,1%). Most of these variants affected DNA damage repair pathways [57% homologous recombination repair (HR), 15% mismatch repair (MMR)]. Besides, double variants in HR and HR pathway were found in 8 patients, HR and MMR pathway were found in 5 patients. Surprisingly, the 50-year-old man with colorectal cancer with three pathogenic variants of the [ FH - BRCA2- FANCD2] genes showed a high aggregation of tumors associated with leiomyomatosis and renal cell cancer and HBOC. Conclusions: We found over 56.5% patients with multiple pathogenic variants in DNA damage repair pathways, which may have important implications for the treatment strategy for these patients. Next-generation sequencing technologies now provide the opportunity to perform simultaneous parallel testing of large numbers of inherited cancer genes, which could guide the clinician as to what the effect of each combination of mutations might be.
Aumolertinib plus apatinib versus aumolertinib as first-line treatment in patients with EGFR mutation–positive locally advanced or metastatic non–small cell lung cancer (NSCLC).
Authors: Fan Zhang, Yi Hu, Xiao Han, ZhiSong Hu
Journal: Journal of Clinical Oncology (2022)

TPS9151 Background: Currently, EGFR-TKIs are widely accepted as the standard treatment for EGFR-mutant advanced NSCLC; however, acquired resistance is inevitable. Preclinical and clinical evidence has demonstrated that dual blockade of the EGFR and VEGF pathways is a viable strategy in the EGFR-mutant advanced NSCLC population to overcome the resistance to EGFR-TKIs. Aumolertinib (HS-10296) is a novel, third-generation EGFR-TKI approved in China to treat EGFR mutation positive non-small cell lung cancer. Apatinib is a small-molecule tyrosine kinase inhibitor that has promising anti-angiogenesis and antitumor activity for NSCLC. Here, we aimed to evaluate the safety and anticancer activity of aumolertinib alone/with apatinib for advanced/metastatic NSCLC patients with EGFR mutation. Methods: The phase III, multicenter, randomized, open-label, controlled study is evaluating the efficacy and safety of aumolertinib plus apatinib versus aumolertinib alone as first line therapy in adult patients with EGFR+ NSCLC. Adult patients with histologically confirmed stage IIIB/IV NSCLC harboring EGFR mutations without prior EGFR TKI treatment are eligible for this study. The performance status (Eastern Cooperative Oncology Group) is 0 or 1. This trial prepared to enroll approximately 300 patients, which will be randomized (1:1) to receive oral aumolertinib once daily 110 mg or adding apatinib 250 mg a day until assessed progressive disease(PD)，stratified by EGFR mutation (Ex19del /L858R/others) and distant metastases sites (brain/liver/others). The primary endpoint is progression free survival assessed by investigators using Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints are disease control rate, duration of response, overall survival and safety. Adverse effects were graded per CTCAE v.4.03. This trial is registered as ChiCTR2100047453. Results: Recruiting. Conclusions: Recruiting. Clinical trial information: ChiCTR2100047453.
Phase I study of the efficacy and safety of IBI319 in patients with advanced malignant tumors.
Authors: Yi-Long Wu, Jianfeng Zhou, Qing Zhou, Huilai Zhang, Kefeng Ding, Jianying Zhou, Shuyan Wang, Wenting Ji, Chengli Zhang, Yanqi Wang, Ping Ni
Journal: Journal of Clinical Oncology (2022)

2646 Background: IBI319 is a recombinant fully human anti-CD137/PD-1 bispecific antibody. In preclinical studies, IBI319 demonstrated a better anti-tumor efficacy and safety. Here we report the initial results from the first-in-human study of IBI319 in patients with advanced malignancies. Methods: Enrolled patients (pts), ECOG PS ≤ 1, had advanced solid tumors or hematological malignancies and failed standard treatment. This phase 1 monotherapy dose-escalation includes accelerated titration (0.03 and 0.1mg/kg) and conventional 3+3 dose escalation (0.3, 1.0, 3.0, 6.0 and 10.0 mg/kg). IBI319 is administered intravenously every 14 days after dose-limiting toxicity (DLT) evaluation. Objectives include evaluation of safety, DLT, pharmacokinetic (PK) and antitumor activity. Adverse events (AEs) were reported per CTCAE v5.0 and DLTs evaluated within a 28-day window. Results: At cutoff date of February 10, 2022, 21 pts were enrolled (median age 55 years; 81.0% male; 19.1% ECOG PS 1; 52.4% advanced solid tumors). The following dose levels have been evaluated; 0.03 mg; 0.1 mg; 0.3 mg; 1 mg; 3 mg and 6 mg. Dose escalation is ongoing. The maximum tolerated dose has not been reached. Treatment-emergent adverse events (TEAEs) was reported in 15 out of 21 (71.4%) pts, among which 1 pts had back pain and nausea of grade 3. The most common TEAEs ( &gt; 10%) were interleukin level increased (6 pts, 28.6%) and C-reactive protein increased (3 pts, 14.3%). Eleven pts (52.4%) experienced treatment-related AEs; none were grade 3 or higher. The most common TRAEs ( &gt; 10%) were interleukin level increased (6 pts, 28.6%) and C-reactive protein increased (3 pts, 14.3%). Importantly, no drug-related elevations in transaminases (ALT, AST) or bilirubin have been seen. No DLT was observed. PK analysis of IBI319 demonstrated consistent exposure with linear PK. For 14 evaluable pts, 1 classical Hodgkin lymphoma patient achieved PR as best response. Conclusions: IBI319 demonstrates good tolerability in patients with advanced solid tumors or hematological malignancies, with a safety profile characterized by a lack of hepatotoxicity frequently observed with CD137-targeting antibodies. Clinical trial information: NCT04708210.
Molecular reflex testing in non-small cell lung cancer: An optimal approach?
Authors: Kari Hooper, Toni Witten, Benjamin Leader, Yuri Anthony Fesko, Mark Kruzel
Journal: Journal of Clinical Oncology (2022)

3127 Background: Molecular testing of non-squamous non-small cell lung cancer (NSCLC) tumors can guide appropriate treatment decisions and improve patient outcomes, but guideline complexity and frequent revision may negatively affect adherence. To assist oncologists in making timelier informed treatment decisions, we implemented a pathologist-directed molecular reflex pathway for non-squamous NSCLC at our clinical laboratory. Testing patterns and adherence to NCCN testing guidelines before and after implementation were reviewed. Methods: This retrospective cohort analysis included patients with diagnosed NSCLC who had molecular testing performed without a molecular reflex testing pathway in place (April 2016-March 2018, cohort A) and after the pathway was implemented (April 2018-March 2020, cohort B) at our clinical laboratory. TATs were calculated using dates of biopsy specimen submission and of molecular testing completion. Molecular testing methods (e.g., polymerase chain reaction, next-generation sequencing [NGS]), genetic alterations tested for and identified, PD-L1 by immunohistochemistry, and specimen quantity not sufficient (QNS) for testing were obtained from patients’ clinical laboratory reports. NSCLC diagnosis and cancer stage were obtained from electronic medical records, and adherence to NCCN guidelines (i.e., under-tested, over-tested genetic alterations) was evaluated according to specimen submission. Results: The mean TAT was 35.1 days for cohort A (n = 123) and 15.8 days for cohort B (n = 168), though the median in both was 14 with a range of 6 – 674 days in cohort A and 9 – 44 in cohort B (Table).Targetable genetic alterations were identified in 12.4% of patients in cohort A and 61.3% in cohort B; 46.3% in cohort A and 60.1% in cohort B had ≥1% positive PD-L1 staining. QNS results declined from 16.7% (n = 20) in cohort A to 12.5% (n = 21) in cohort B. Non-NCCN guideline testing was observed in 86.7% of patients in cohort A and 25.6% in cohort B, with those in cohort A being primarily under-tested (70%) and those in cohort B being over-tested. Only 13.3% of cohort A had alignment with NCCN guidelines for appropriate time of testing. Conclusions: Implementation of a pathology-driven molecular reflex pathway for non-squamous NSCLC was associated with increased identification of potentially targetable genetic alterations and improved adherence to NCCN NSCLC testing guidelines, along with reduction in QNS results. Though the TAT mean decreased after pathway implementation, the median did not change, offsetting the often increased lab TAT for NGS methodology vs. PCR and FISH alone. [Table: see text]
Comparison of methodology in the collection of gender and race/ethnicity in hematology and oncology journal editorial boards.
Authors: Shruti Rajesh Patel, Ivy Riano, Inas Abuali, Angela Ai, Gabriella Geiger, Jacqueline Pimienta, Adriana C. Ramirez Roggio, Natasha Dhawan, Alexandra Lizette Salinas, Narjust Duma, Nazli Dizman
Journal: Journal of Clinical Oncology (2022)

11061 Background: Reporting on disparities is strongly influenced by the methodology used to collect race/ethnicity and gender data. Incorporating gender and race into research has its challenges, as these variables are difficult to define. As underrepresentation of minorities and women continues to persist in many facets of academia, it is important to assess the accuracy of differing methodologies. While asking individuals to self-identify their race and gender remains the gold standard of reporting, low response rates and response bias have been shown to affect results. In our initial study on representation in editorial boards, gender and race/ethnicity were determined based on publicly available data which can lead to misclassification of editors. We aimed to add to our study by asking editors to self-report their gender and race in hopes to validate our methodology given the importance of considering gender and race in academia. Methods: Of the 60 highest impact journals in oncology, hematology, radiation oncology, and surgical oncology identified, race/ethnicity and gender determinations were made using two methods. All senior editors were sent a survey via email asking participants to self-report their gender, race/ethnicity, age, and job characteristics. Gender and race were also assigned to the editors by a diverse coding team based on publicly available data and the NIH's OMB Directive 15 as a framework. The self-reported data was then compared to data that was assigned by our team. Results: 66 of the 793 (8.3%) editorial board members included in the study responded to the survey. Of the 66 respondents, gender was assigned correctly 100% (66/66) of the time and race was assigned correctly 95.5% (63/66) of the time. Of the 66 respondents to the self-survey of the 793 editorial board members surveyed. A significantly lower proportion of men responded to the survey compared to the gender breakdown of the 793 editorial board members (54.5% vs 72.6%; p = 0.000279). The three incorrectly identified respondents self-identified as Native Hawaiian, White, and Middle Eastern. Conclusions: Multiple recent reports have demonstrated high rates of sexual harassment, gender bias, and exclusion in the field of oncology. Collecting data on racial/ethnic groups and gender is imperative to understand the academic landscape of oncology and work towards a more equitable environment. Notably, this data from our study supports the methodology of a diverse coding team assigning gender and race based on publicly available data and the NIH's OMB Directive 15 as a framework as an alternative to self-report. Our study also demonstrates the low response rates and significant discrepancies in the demographic of respondents seen in survey-based identification.